The Role of Retrovirus Structural Proteins in Viral Replication

The research in our laboratory is focused upon understanding the contributions of retroviral structural proteins to the virus life cycle. Retroviruses are agents of human and animal diseases, causing immunodeficiencies (including AIDS), leukemias, lymphomas, other malignancies, and wasting syndromes. Despite nearly a century of study, there are many gaps in our understanding of the basic processes of retroviral replication. Our laboratory specifically has focused upon the activities of the Gag protein in forming virus particles during the assembly phase of infection and of the CA protein in facilitating the early steps of genome replication.

The CA protein is one of the least understood components of the retrovirus. It is well established that CA is the major structural element of the virus core. However, in addition, numerous studies indicate that its integrity is important for the events of genome replication, carried out by the reverse transcriptase enzyme packaged into the virion with the genome. There are, however, no adequate models to explain how it acts. We have conducted an extensive genetic analysis of CA function with a special focus on its most highly conserved amino acid motif. This work has indicated that this region of the protein is likely critical for its ability to assemble itself into a two-dimensional array of protein subunits known as the capsid shell. It also appears that these residues may participate in interactions with the reverse transcription complex in the interior of the capsid in a manner that is essential for effective genome replication. A major focus of our present work, therefore, is the dissection of the intermolecular interactions in which the CA protein is involved. This includes CA self-interaction to form the virus particle itself, interactions with host factors including the tryptophanyl tRNA synthetase, and the possible interaction of CA with other viral components of the reverse transcription complex (specifically viral RNA and reverse transcriptase). Genetic, biochemical, molecular biological and structural approaches will be used. Identification of the specific activities of CA will provide critical information needed for understanding the establishment of infection and oncogenesis by retroviruses, the transposition of retrotransposons and endogenous retroviruses in the human genome, and the mechanism of gene delivery by retroviral vectors. It may also provide a new target for the design of much-needed anti-retroviral strategies.